Pulmicort Flexhaler

CLINICAL PHARMACOLOGY

Mechanism of Action

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid
activity and weak mineralocorticoid activity. In standard in vitroand
animal models, budesonide has approximately a 200-fold higher affinity for the
glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency
than cortisol (rat croton oil ear edema assay). As a measure of systemic activity,
budesonide is 40 times more potent than cortisol when administered subcutaneously
and 25 times more potent when administered orally in the rat thymus involution
assay. The clinical significance of this is unknown.

The activity of PULMICORT FLEXHALER (budesonide inhalation powder) is due to the parent drug, budesonide.
In glucocorticoid receptor affinity studies, the 22R form was two times as active
as the 22S epimer. In vitro studies indicated that the two forms of budesonide
do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in asthma is
not known. Inflammation is an important component in the pathogenesis of asthma.
Corticosteroids have a wide range of inhibitory activities against multiple
cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes)
and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved
in allergic and non-allergic-mediated inflammation. These anti-inflammatory
actions of corticosteroids may contribute to their efficacy in asthma.

Studies in asthmatic patients have shown a favorable ratio between topical
anti-inflammatory activity and systemic corticosteroid effects over a wide range
of doses of inhaled budesonide. This is explained by a combination of a relatively
high local anti-inflammatory effect, extensive first pass hepatic degradation
of orally absorbed drug (85-95%), and the low potency of formed metabolites
(see below).

Pharmacodynamics

To confirm that systemic absorption is not a significant factor in the clinical
efficacy of inhaled budesonide, a clinical study in patients with asthma was
performed comparing 400 mcg budesonide administered via a pressurized metered-dose
inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study
demonstrated the efficacy of inhaled budesonide but not orally administered
budesonide, even though systemic budesonide exposure was comparable for both
treatments, indicating that the inhaled treatment is working locally in the
lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide
are largely explained by its direct action on the respiratory tract.

Inhaled budesonide has been shown to decrease airway reactivity in various
challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical
relevance of these models is not certain.

HPA Axis effects: The effects of inhaled budesonide on the hypothalamic-pituitary-adrenal
(HPA) axis were studied in 905 adults and 404 pediatric patients with asthma.
For most patients, the ability to increase cortisol production in response to
stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact
with inhaled budesonide treatment at recommended doses. For adult patients treated
with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13%
respectively, had an abnormal stimulated cortisol response (peak cortisol <
14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test)
as compared with 8% of patients treated with placebo. Similar results were obtained
in pediatric patients. In another study in adults, doses of 400, 800 and 1600
mcg of inhaled budesonide twice daily for 6 weeks were examined; 1600 mcg twice
daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated
cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction.
In this study, no patient taking doses of 400 and 800 mcg twice daily met the
criterion for an abnormal stimulated cortisol response (peak cortisol < 14.5
mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label,
long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal
effect on the HPA axis (both basal and stimulated plasma cortisol) of inhaled
budesonide when administered at doses ranging from 100 to 800 mcg twice daily.
In patients who had previously been oral steroid-dependent, use of inhaled budesonide
at doses ranging from 100 to 800 mcg twice daily was associated with higher
stimulated cortisol response compared with baseline following 1 year of therapy.

Pharmacokinetics

Absorption

After oral administration of budesonide, peak plasma concentration was achieved
in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast,
most of budesonide delivered to the lungs is systemically absorbed. In healthy
subjects, 34% of the metered dose was deposited in the lungs (as assessed by
plasma concentration method and using a different budesonide containing dry-powder
inhaler) with an absolute systemic availability of 39% of the metered dose.
Peak steady-state plasma concentrations of budesonide delivered from PULMICORT
FLEXHALER in adults with asthma (n=39) occurred at approximately 10 minutes
post-dose and averaged 0.6 and 1.6 nmol/L at doses of 180 mcg once daily and
360 mcg twice daily, respectively.

In asthmatic patients, budesonide showed a linear increase in AUC and Cmax
with increasing dose after both a single dose and repeated dosing of inhaled
budesonide.

Distribution

The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90%
bound to plasma proteins. Protein binding was constant over the concentration
range (1-100 nmol/L) achieved with, and exceeding, recommended doses of PULMICORT
FLEXHALER. Budesonide showed little or no binding to corticosteroid binding
globulin. Budesonide rapidly equilibrated with red blood cells in a concentration
independent manner with a blood/plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that budesonide is
rapidly and extensively metabolized. Two major metabolites formed via cytochrome
P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated
and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide.
The corticosteroid activity of each of these two metabolites is less than 1%
of that of the parent compound. No qualitative differences between the in
vitro and in vivo metabolic patterns have been detected. Negligible metabolic
inactivation was observed in human lung and serum preparations.

Excretion/Elimination

The 22R form of budesonide was preferentially cleared by the liver with systemic
clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life,
2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide
was excreted in urine and feces in the form of metabolites. Approximately 60%
of an intravenous radiolabeled dose was recovered in the urine. No unchanged
budesonide was detected in the urine.

Special Populations

No clinically relevant pharmacokinetic differences have been identified due
to race, sex, or advanced age.

Geriatric

The pharmacokinetics of PULMICORT FLEXHALER (budesonide inhalation powder) in geriatric patients have not
been specifically studied.

Pediatric

Following intravenous dosing in pediatric patients age 10-14 years, plasma
half-life was shorter than in adults (1.5 hours vs. 2.0 hours in adults). In
the same population following inhalation of budesonide via a pressurized metered-dose
inhaler, absolute systemic availability was similar to that in adults.

Peak steady-state plasma concentrations of budesonide delivered via PULMICORT
FLEXHALER in children and adolescents with asthma (n=14) occurred at approximately
15 to 30 minutes post-dose and averaged 0.4 and 1.5 nmol/L at doses of 180 mcg
once daily and 360 mcg twice daily, respectively.

Nursing Mothers

The disposition of budesonide when delivered by inhalation from a dry powder
inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied
in eight lactating women with asthma from 1 to 6 months postpartum. Systemic
exposure to budesonide in these women appears to be comparable to that in non-lactating
women with asthma from other studies. Breast milk obtained over eight hours
post-dose revealed that the maximum concentration of budesonide for the 400
and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within
45 minutes after dosing. The estimated oral daily dose of budesonide from breast
milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose
regimens used in this study, which represents approximately 0.3% to 1% of the
dose inhaled by the mother. Budesonide levels in plasma samples obtained from
five infants at about 90 minutes after breastfeeding (and about 140 minutes
after drug administration to the mother) were below quantifiable levels ( <
0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use
In Specific Populations, Nursing Mothers].

Renal or Hepatic Insufficiency

There are no data regarding the specific use of PULMICORT FLEXHALER (budesonide inhalation powder) in patients
with hepatic or renal impairment. Reduced liver function may affect the elimination
of corticosteroids. The pharmacokinetics of budesonide were affected by compromised
liver function as evidenced by a doubled systemic availability after oral ingestion.
The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic
patients and in healthy subjects.

Cimetidine: At recommended doses, cimetidine, a nonspecific inhibitor
of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics
of oral budesonide.

Animal Toxicology

Reproductive Toxicology Studies

As with other corticosteroids, budesonide was teratogenic and embryocidal in
rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately
0.3 times the maximum recommended daily inhalation dose in adults on a mcg/m²
basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 3 times
the maximum recommended daily inhalation dose in adults on a mcg/m² basis).
No teratogenic or embryocidal effects were observed in rats when budesonide
was administered by inhalation at doses up to 250 mcg/kg (approximately equivalent
to the maximum recommended daily inhalation dose in adults on a mcg/m²
basis).

Clinical Studies

Asthma

The safety and efficacy of PULMICORT FLEXHALER (budesonide inhalation powder) were evaluated in two 12-week, double-blind, randomized, parallel-group, placebo-controlled clinical studies
conducted at sites in the United States and Asia involving 1137 patients aged
6 to 80 years with mild to moderate asthma. Study 1 evaluated PULMICORT FLEXHALER (budesonide inhalation powder)
180 mcg, PULMICORT TURBUHALER 200 mcg, and placebo, each administered as 1 inhalation
once daily or 2 inhalations twice daily in patients 18 years of age and older
with mild to moderate asthma previously treated with inhaled corticosteroids.
The delivered dose of PULMICORT FLEXHALER (budesonide inhalation powder) 180 mcg and PULMICORT TURBUHALER 200
mcg are the same; each delivers 160 mcg from the mouthpiece. Study 2 evaluated
PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 2 inhalations once daily or 4 inhalations twice
daily, PULMICORT TURBUHALER 200 mcg, 1 inhalation once daily or 2 inhalations
twice daily, and placebo in pediatric patients aged 6 to 17 years with mild
to moderate asthma. Both of the studies had a 2-week placebo treatment run-in
period followed by a 12-week randomized treatment period. The primary endpoint
was the difference between baseline and the mean of the treatment-period FEV1
(adults) or FEV1 % predicted (children).

Footnote: PULMICORT TURBUHALER; a different PULMICORT DPI Statistical
model is analysis of covariance with treatment and region (US/Asia) as factors
and the baseline value as the covariate.

Patients 6 to 17 years of age (Study 2)

This study enrolled 516 patients aged 6 to 17 years with mild asthma (mean
baseline % predicted FEV1 84.9%). The study population included patients
previously treated with inhaled corticosteroids for no more than 30 days before
the study began (4%) and patients who were na´ve to inhaled corticosteroids
(96%). Mean change from baseline in % predicted FEV1 during the 12-week
treatment period in the PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 4 inhalations twice daily
treatment group was 5.6 compared with 0.2 in the placebo group (p < 0.001).
Secondary endpoints of morning and evening PEF showed differences from baseline
favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001).